JP7008084B2 - How to improve the chemical stability of pregabalin by controlling the particle size - Google Patents

Description

The present invention relates to a pharmaceutical product containing pregabalin as a drug substance, and discloses a detailed method for improving the chemical stability of the drug substance under its storage conditions.

Pregabalin (generic name) is a derivative of γ-aminobutyric acid (GABA), whose chemical name is described as (3S) -3-aminomethyl-5-methylcaproic acid. Pregabalin is a useful drug for the treatment of neuropathic pain and pain associated with fibromyalgia. (Refer to Non-Patent Document 1 etc.).

Currently, pregabalin is provided in the form of capsules or orally disintegrating tablets to medical practice in Japan. The formulation and manufacturing method of the preparation containing pregabalin are introduced in the following prior documents such as Patent Documents 1 to 7, and it is pointed out that it is difficult to ensure the chemical stability of pregabalin in the preparation. ing.

The present inventor has repeatedly studied the above-mentioned prior art with the aim of developing a new technique for improving the chemical stability of pregabalin contained in the pharmaceutical product.

Japanese Patent No. 4334610 Special Table 2017-510599 Special Table 2011-504491 Special Table 2010-524991 Chinese Patent Application Publication No. 106606495 Chinese Patent Application Publication No. 104288106 Chinese Patent Application Publication No. 1049006064

"Lyrica (Registered Trademark) Capsule OD Tablets 25mg / 75mg / 150mg" Pharmaceutical Interview Form Revised June 2017 (10th edition)

It is an object of the present invention to provide a technical means for producing a solid preparation having improved chemical stability of pregabalin.

As a result of diligent studies to solve the above problems, the present inventor has determined the chemical stability of pregabalin when the particle size distribution, etc. (particle size distribution or volume average diameter) of pregabalin is controlled within a predetermined range. Etc. were found to be unexpectedly significantly superior. The present inventor has made further diligent studies based on the findings, and has completed the following invention.

The present invention is a method for producing pregabalin or a preparation using the same, in which the particle size distribution and the like are controlled within a predetermined range, and the preferred configurations thereof are described in the following (1) to (8).
(1) Cumulative 50% particle diameter (d50) measured by the laser diffraction / scattering method is 9.0 μm or more (preferably 15.0 μm or more) in volume-based measurement, and cumulative 90% particle diameter in volume-based measurement. A particle size distribution in which (d90) is 30.0 μm or more (preferably 50.0 μm or more), and the cumulative 10% particle size (d10) in volume-based measurement is 3.0 μm or more (preferably 5.0 μm or more). A method for producing a solid preparation using pregavalin or a pharmaceutically acceptable salt thereof, which is characterized by having (or having a volume average diameter of 13.0 μm or more, preferably 22.0 μm).
(2) The production method according to (1) above, wherein the solid preparation is a tablet (preferably an orally disintegrating tablet).
(3) The above-mentioned (1) including a step of granulating (preferably dry granulation such as melt granulation) of pregabalin having the particle size distribution according to the above (1) or a pharmaceutically acceptable salt thereof. ) Or the manufacturing method according to (2).
(4) Dry granulation (preferably melting) of pregavalin having the particle size distribution according to (1) above or a pharmaceutically acceptable salt thereof together with a low melting point fat or oil such as a fatty acid ester (preferably glycerin fatty acid ester). The production method according to (3) above, which comprises a step of granulating).
(5) Pregabalin or a pharmaceutically acceptable salt thereof in pregabalin or pharmaceutically acceptable pregabalin in an amount of 90.0 % by weight or more based on the total weight of the granulated product. The production method according to (3) or (4) above, which comprises a step of producing a product containing an acceptable salt.
(6) The above-mentioned (3) to the above-mentioned (3) to include a step of tableting a mixture obtained by mixing a granule containing pregabalin or a pharmaceutically acceptable salt thereof together with an excipient and a lubricant. The manufacturing method according to any one of (5).
(7) The cumulative 50% particle diameter (d50) in the volume-based measurement measured by the laser diffraction / scattering method is 15.0 μm or more, and the cumulative 90% particle diameter (d90) in the volume-based measurement is 50.0 μm. A solid preparation containing pregavalin or a pharmaceutically acceptable salt thereof, which is characterized by having the above-mentioned particle size distribution.
(8) The cumulative 50% particle diameter (d50) in the volume-based measurement measured by the laser diffraction / scattering method is 15.0 μm or more, and the cumulative 90% particle diameter (d90) in the volume-based measurement is 50.0 μm. (7) The above (7), which comprises a granulated product containing pregavalin or a pharmaceutically acceptable salt thereof characterized by having the above-mentioned particle size distribution and a low melting point oil (preferably a fatty acid ester). The solid formulation described in.

According to the present invention, it is possible to provide a solid preparation having further improved chemical stability of pregabalin and a method for producing the same.

The solid preparation according to one embodiment of the present invention contains pregabalin or a pharmaceutically acceptable salt thereof as an active ingredient. The solid preparation and the method for producing the solid preparation will be described in detail below. However, the following description is an example for explaining the present invention, and does not mean that the technical scope of the present invention is limited only to this description range. In this specification, when a numerical range is indicated by using "-", the numerical values at both ends thereof are included.

<Form of solid product>
The dosage form of the solid preparation according to the present embodiment is preferably granules, capsules, tablets or the like, more preferably tablets, and uncoated tablets (film coating layer, sugar-coated layer, etc.) in order to be provided to the medical field. It refers to a tablet that is not covered with and is still molded by tableting or the like. The same shall apply hereinafter) is more preferable.

The above-mentioned tablets are provided as uncoated tablets or after being coated with a film-coated layer containing a coating agent to form film-coated tablets and then provided to medical sites. The shape of the tablet may be any of a circular tablet, a circular R tablet, a circular angle tablet, a circular two-stage R tablet, a deformed tablet (oval tablet, etc.) and the like.

The dosage form of the tablet is preferably an orally disintegrating tablet, and more preferably an orally disintegrating tablet which is an uncoated tablet. The orally disintegrating tablet is provided as a tablet that disintegrates rapidly in the oral cavity, and is provided separately from ordinary tablets, and has an orally disintegrating time of less than 60 seconds, preferably less than 40 seconds.

<Primitive drug>
The solid preparation according to the present embodiment uses pregabalin or a pharmaceutically acceptable salt thereof whose particle size distribution is controlled within a predetermined range from the viewpoint of chemical stability of pregabalin as a drug substance. It is characterized by that.

The cumulative 10% particle size (d10) of pregabalin or a pharmaceutically acceptable salt thereof in volume-based measurement is preferably 3.0 μm or more, more preferably 5.0 μm or more, still more preferably 6.0 μm or more. , 7.0 μm or more is particularly preferable. Further, from a practical point of view such as in the production of tablets, 50.0 μm or less is preferable, 45.0 μm or less is more preferable, 35.0 μm or less is further preferable, and 25.0 μm or less is particularly preferable.

The cumulative 50% particle size (d50) of pregabalin or a pharmaceutically acceptable salt thereof in volume-based measurement is 9.0 μm or more, preferably 15.0 μm or more, more preferably 20.0 μm or more. 30.0 μm or more is more preferable, and 40.0 μm or more is particularly preferable. Further, from a practical point of view such as in the production of tablets, 250.0 μm or less is preferable, 220.0 μm or less is more preferable, 150.0 μm or less is further preferable, and 100.0 μm or less is particularly preferable.

The cumulative 90% particle size (d90) of pregabalin or a pharmaceutically acceptable salt thereof in volume-based measurement is 30.0 μm or more, preferably 50.0 μm or more, more preferably 80.0 μm or more. 110.0 μm or more is more preferable, and 140.0 μm or more is particularly preferable. Further, from a practical point of view such as in the production of tablets, 600.0 μm or less is preferable, 550.0 μm or less is more preferable, 400.0 μm or less is further preferable, and 300.0 μm or less is particularly preferable.

The volume average diameter of pregabalin or a pharmaceutically acceptable salt thereof is preferably 13.0 μm or more, more preferably 22.0 μm or more, further preferably 45.0 μm or more, and particularly preferably 57.0 μm or more. Further, from a practical point of view such as in the production of tablets, 400.0 μm or less is preferable, 350.0 μm or less is more preferable, 290.0 μm or less is further preferable, and 200.0 μm or less is particularly preferable.

The pregavalin or a pharmaceutically acceptable salt thereof used in the present embodiment preferably has a particle size distribution or a volume average diameter larger than that of Comparative Example 1 below, and the above particle size distribution or volume average diameter. It is more preferable to have both the above particle size distribution and the volume average diameter. In this embodiment, the particle size distribution and the volume average diameter can be measured by a laser diffraction / scattering method, and the detailed measurement conditions thereof are the dry measurement described in the following examples. It is possible to follow things.

The solid preparation according to the present embodiment contains pregabalin as a drug substance or a pharmaceutically acceptable salt thereof, and is preferably a single agent containing no other drug substance.

The "pregabalin or a pharmaceutically acceptable salt thereof" in the present embodiment includes its free form (amphoteric ion) and its pharmaceutically acceptable complex, salt, solvate, hydrate, and the like. Any pharmaceutically acceptable form of pregabalin, including polyforms, may be utilized. Salts include, but are not limited to, acid-added salts and base-added salts, including hemisalts.

Pharmaceutically acceptable acid addition salts are obtained from inorganic acids (eg, hydrochloric acid, nitrate, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phobic acid, etc.). Non-toxic salts and non-toxic salts obtained from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkano acids, hydroxy alkano acids, alkandic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Can be included. Potentially useful salts include acetate, asparagate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, besilate, bicarbonate, carbonate, bicarbonate, Sulfates, pyrosulfates, hydrogen sulfites, sulfites, borates, cansilates, capricates, citrates, edicylates, escillates, formates, fumarates, gluceptates, gluconates, Glucronate, hexafluorophosphate, hibenzate, hydrochloride, chloride, hydrobromide, bromide, hydroiodide, iodide, isethionate, isobutyrate, lactate, malic acid Salt, maleate, malonate, mandelate, mesylate, methylsulfate, naphthylate, 2-napsilate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, Phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, phthalate, propionate, saccharate, sevacinate, stearate, sverate, succinate , Tartrate, tosylate, trifluoroacetate and the like.

Pharmaceutically acceptable base addition salts can include non-toxic salts obtained from bases containing metal cations (eg, alkali metal cations or alkaline earth metal cations) and amines. Examples of potentially useful salts are aluminum, arginine, N, N'-dibenzylethylenediamine, calcium, chloroprocine, choline, diethanolamine, diethylamine, dicyclohexylamine, ethylenediamine, glycine, lysine, magnesium, N-methylglue. Includes, but is not limited to, camine, olamine, potassium, prokine, sodium, tromethamine, zinc and the like.

Pregavalin or a pharmaceutically acceptable salt thereof is preferably 10.0 to 90.0% by weight, more preferably 20.0 to 80% by weight, based on the total weight of the solid preparation (preferably uncoated tablets). In the solid preparation in the range of 0% by weight, more preferably 20.0 to 60.0% by weight, still more preferably 25.0 to 50.0% by weight, and particularly preferably 25.0 to 40.0% by weight. It is contained in. Examples of the content of pregabalin per tablet when the solid preparation is a tablet include 25 mg, 75 mg, and 150 mg.

<Additives>
Pharmaceutically acceptable additions of excipients, binders, disintegrants, lubricants, coatings and the like commonly used in the manufacture of pharmaceuticals to produce the solid formulations according to this embodiment. Agents can also be used. Further, it is preferable to use a low melting point fat or oil as an additive. In this specification, the interpretation of the terms of various additives (excipients, binders, disintegrants, lubricants, coating agents, low melting point oils and fats, etc.) is used as the additives in the formulation. It is preferable to understand that it is used with the expectation that it is essential to exert its role, and as a result, it also fulfills its role as an additive. Also, of course, no drug substance is included in the interpretation of the terms of the additives herein.

<Excipient>
The excipient is specifically selected from lactose hydrate, crystalline cellulose, anhydrous lactose, D-mannitol, isomalt, erythritol, starch (corn starch, etc.), cyclodextrin and the like, preferably D-mannitol and /. Or starch. These excipients may be used alone or in combination of two or more.

The content of the excipient with respect to the total weight of the solid preparation (preferably uncoated tablet) is preferably 10.0% by weight or more, more preferably 20.0% by weight or more, still more preferably 25.0% by weight or more, and 30. It is more preferably 0.0% by weight or more, and particularly preferably 40.0% by weight or more. The content is preferably 90.0% by weight or less, more preferably 80.0% by weight or less, further preferably 75.0% by weight or less, further preferably 70.0% by weight or less, and 65.0% by weight. % Or less is particularly preferable.

<Binder>
Specific examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), methyl cellulose, polyvinylpyrrolidone (povidone), ethyl cellulose, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol / graft copolymer, polyethylene glycol, methacrylic acid copolymer, and acrylic. Examples thereof include a dispersion of ethyl acetate / methyl methacrylate copolymer. These binders may be used alone or in combination of two or more.

The content of the binder with respect to the total weight of the solid preparation (preferably uncoated tablets) is preferably 0.1% by weight or more, more preferably 0.2% by weight or more, still more preferably 0.5% by weight or more. 0% by weight or more is particularly preferable. The content is preferably 10.0% by weight or less, more preferably 8.0% by weight or less, further preferably 5.0% by weight or less, and particularly preferably 4.0% by weight or less. When the solid preparation is produced by a dry granulation method (preferably a melt granulation method), even if the content of the binder is less than 1.0% by weight (preferably less than 0.1% by weight). Well, it does not have to contain a binder.

<Disintegrant>
Specific examples of the disintegrant include low-degree-of-substitution hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropyl starch, carboxymethyl starch sodium, and crospovidone. These disintegrants may be used alone or in combination of two or more.

The content of the disintegrant with respect to the total weight of the solid preparation (preferably uncoated tablets) is preferably 1.0% by weight or more, more preferably 2.0% by weight or more, still more preferably 2.5% by weight or more. 0% by weight or more is particularly preferable. The content is preferably 20.0% by weight or less, more preferably 15.0% by weight or less, further preferably 12.0% by weight or less, and particularly preferably 10.0% by weight or less.

<Glidant>
Specific examples of the lubricant include light anhydrous silicic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc and the like, and magnesium stearate is preferable. These lubricants may be used alone or in combination of two or more.

The content of the lubricant with respect to the total weight of the solid preparation (preferably uncoated tablets) is preferably 0.1% by weight or more, more preferably 0.2% by weight or more, further preferably 0.5% by weight or more, and 0. It is more preferably 8.8% by weight or more, and particularly preferably 1.0% by weight or more. The content is preferably 5.0% by weight or less, more preferably 4.0% by weight or less, further preferably 3.0% by weight or less, further preferably 2.5% by weight or less, and 2.0% by weight. % Or less is particularly preferable.

<Low melting point fats and oils>
The low melting point fat and oil used in the present embodiment preferably has a melting point of 20 to 90 ° C., more preferably 30 to 85 ° C., further preferably 40 to 80 ° C., and 45 to 69 ° C. Especially preferable. The low melting point fat and oil can be uniformly blended with the active ingredient as compared with the high melting point fat and oil, and as a result, a more stable solid preparation in which the decomposition of pregabalin, which is the active ingredient, is suppressed can be obtained. Specific examples of low melting point oils and fats include higher fatty acids (for example, 10 to 40 carbon atoms, preferably 12 to 26 carbon atoms) and salts thereof, and higher alcohols (for example, 10 to 40 carbon atoms, preferably 12 to 26 carbon atoms). , Hydrocarbons (paraffin wax, microcrystallin wax, etc.), fatty acid esters, hardened oils (hardened castor oil, hardened soybean oil, hardened rapeseed oil, hardened cotton seed oil, etc.), alkylene oxide polymers (polyethylene glycol, polypropylene glycol, etc.) And the like, fatty acid esters are preferable, and fatty acid esters of polyhydric alcohols are more preferable. These low melting point fats and oils may be used alone or in combination of two or more.

As used herein, the term "fatty acid ester of polyhydric alcohol" means a compound in which some or all of the hydroxyl groups of the polyhydric alcohol are esterified with a fatty acid (preferably a fatty acid having 12 to 26 carbon atoms). The polyhydric alcohol portion of the "polyhydric alcohol fatty acid ester" includes alkylene glycols such as ethylene glycol, propylene glycol, butanediol and pentandiol; polyalkylene glycols such as polyethylene glycol and polypropylene glycol; glycerin, sorbitol, sorbitan and penta. Examples thereof include saccharides such as erythritol and sucrose, and glycerin is preferable. Specific examples of the "fatty acid ester of polyvalent alcohol" include ethylene glycol fatty acid ester, propylene glycol fatty acid ester, glycerin fatty acid ester, polyoxyalkylene fatty acid ester, sorbitan fatty acid ester, polyoxyalkylene sorbitan fatty acid ester, and polyoxyalkylene. Examples thereof include sorbitol fatty acid ester and sucrose fatty acid ester, and glycerin fatty acid ester is preferable, monofatty acid (C12-26) glyceryl is more preferable, and glycerin monostearate is particularly preferable. The fatty acid esters of these polyhydric alcohols may be used alone or in combination of two or more.

The content of the low melting point oil / fat with respect to the total weight of the solid preparation (preferably uncoated tablets) is preferably 0.1% by weight or more, more preferably 0.5% by weight or more, still more preferably 1.0% by weight or more. It is more preferably 5.5% by weight or more, and particularly preferably 2.0% by weight or more. The content is preferably 10.0% by weight or less, more preferably 8.0% by weight or more, further preferably 6.0% by weight or less, still more preferably 5.0% by weight or less, and further preferably 4.8% by weight. % Or less is particularly preferable.

<Granulation>
The solid preparation according to the present embodiment preferably contains a granulated product containing pregabalin or a pharmaceutically acceptable salt thereof. The granulated product is preferably 10.0 to 90.0% by weight, more preferably 20.0 to 80.0% by weight, still more preferably 30 with respect to the total weight of the solid preparation (preferably uncoated tablets). It is contained in the solid preparation in the range of 0.0 to 70.0% by weight, particularly preferably 40.0 to 60.0% by weight.

Further, the granulated product containing pregavalin or a pharmaceutically acceptable salt thereof is preferably 70.0 to 99.0% by weight, more preferably 75.0, based on the total weight of the granulated product. It contains from 98.0% by weight, more preferably 80.0 to 97.0% by weight, even more preferably 85.0 to 96.0% by weight, and particularly preferably 90.0 to 95.0% by weight of pregavalin. Obtained like this.

<Granulation method>
In the production of the solid preparation according to the present embodiment, it is preferable that granulation is performed using pregabalin having the above-mentioned particle size distribution or the like or a pharmaceutically acceptable salt thereof. Examples of the granulation method in the present embodiment include a dry granulation method (crushing granulation method, melt granulation method, etc.) or a wet granulation method (fluidized bed granulation method, stirring granulation method, extrusion granulation method, etc.). .. Of these, the dry granulation method is preferably used, and the melt granulation method is more preferable.

By the above-mentioned granulation method, pregabalin or a pharmaceutically acceptable salt thereof (and optionally an additive) and a low melting point substance are uniformly blended, and a granulated product (preferably a dry granulated product, more preferably) is blended. Is a preferred embodiment in which a molten granulated product) is formed. The chemical stability of pregabalin was further improved by forming a granulated product containing pregabalin or a pharmaceutically acceptable salt thereof whose particle size distribution was controlled within the above range and a low melting point oil / fat. Solid formulations (preferably tablets) can be produced (see Examples 1 and 3-5).

Unlike the wet granulation method, the dry granulation method is characterized in that granulation is performed without adding a solution such as water or alcohol. In the melt granulation method, a drug (pregavalin or a pharmaceutically acceptable salt thereof) and a low melting point fat or oil are added to a stirring granulator, a fluidized bed granulator, or the like (and other additives are added). It may be used.) Then, the low melting point oil and fat is melted by heating while mixing the mixture, and finally the granulated product is formed by cooling. At the time of melt granulation, the temperature is heated to a temperature equal to or higher than the melting point of the low melting point fat (usually 40 to 100 ° C., preferably 50 to 90 ° C., more preferably 60 to 80 ° C., still more preferably 70 to 80 ° C.).

The low melting point fat and oil is preferably 1.0 to 30.0% by weight, more preferably 2.0 to 20.0% by weight, and further preferably 3.0 to 18.0 with respect to the total weight of the granulated product. %, More preferably 4.0 to 15.0%, and particularly preferably 4.5 to 12.0% in the granulated product.

Blending amount of low melting point fats and oils with respect to the blending amount of pregabalin or its pharmaceutically acceptable salt in the granulated product (blending amount of low melting point fats and oils / blending of pregabalin or its pharmaceutically acceptable salt) The amount) is preferably 0.010 or more, more preferably 0.020 or more, further preferably 0.030 or more, and particularly preferably 0.040 or more. In addition, the blending amount of low melting point fats and oils (blending amount of low melting point fats and oils / pregabalin or pharmaceutically acceptable salt thereof) with respect to the blending amount of pregabalin or its pharmaceutically acceptable salt in the granulated product. The blending amount) is preferably 0.40 or less, more preferably 0.20 or less, further preferably 0.18 or less, further preferably 0.15 or more, and particularly preferably 0.12 or less.

<Tablet manufacturing method>
The tablet according to the present embodiment can be produced by a general production method, and can be produced, for example, by the following production method.

First, melt granulation is performed by heating the drug substance, low melting point fats and oils, etc. while stirring to produce granulated products. Then, after the obtained granulated product is sized, it is mixed with an excipient, a lubricant and the like and compression-molded by a tableting machine to obtain a tablet (uncoated tablet). The striking pressure when the uncoated tablet is tableted and manufactured is preferably selected from any numerical value in the range of 600 to 1400 kgf. Further, if desired, a film coating layer may be applied to the obtained uncoated tablets.

Further, by sandwiching the tablet with a packaging sheet and aluminum foil, covering the tablet, and heat-sealing the tablet, a PTP sheet product containing the tablet according to the present embodiment can be obtained. Specific examples of the material used for the packaging sheet include polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene and the like. In order to improve the stability of the tablet of the present invention against humidity, a PTP sheet product may be manufactured using a material having a drying function, a PTP sheet product may be wrapped in an aluminum pillow, or a desiccant may be bottled together with the tablet. It is possible to use a well-known method such as encapsulation in.

Hereinafter, the present invention will be described with reference to Examples and the like, but the present invention is not limited to these Examples and the like. The particle size of pregabalin described in the following Examples and Comparative Examples was measured by a laser diffraction / scattering method. The measurement was performed by dry measurement under the condition of sample refractive index: 1.60.

(Example 1)
Particle size distribution: d10 = 8.0 μm / d50 = 44.8 μm / d90 = 153 μm; Volume average diameter: 63.6 μm powder consisting of pregabalin.

(Example 2)
Particle size distribution: d10 = 43.2 μm / d50 = 212 μm / d90 = 534 μm; Volume average diameter: 259 μm powder made of pregabalin.

(Comparative Example 1)
Particle size distribution: d10 = 2.4 μm / d50 = 7.5 μm / d90 = 25.2 μm; powder consisting of pregabalin having an average volume diameter of 11.1 μm.

(Example 3)
Particle size distribution: d10 = 8.0 μm, d50 = 44.8 μm, d90 = 153 μm; volume average diameter: 63.6 μm, pregabalin 250.0 g, and glycerin monostearate (Rikemar S-manufactured by RIKEN Vitamin Co., Ltd.) 100P, melting point: 63-68 ° C) 12.5g of powder is put into a stirring granulator (VG01 type / manufactured by Paulek Co., Ltd.) and heated to a temperature of 70 ° C to melt glycerin monostearate. The mixture was stirred for 5 minutes (blade rotation speed: 290 rotations / minute, cross screw rotation speed: 3500 rotations / minute) while maintaining the temperature, and then cooled to a temperature of 40 ° C. to obtain a molten granulated product. The obtained molten granules were sized with a 24-mesh sieve.

After mixing 23.6 g of the obtained sizing product and 32.8 g of PEARLITOR (registered trademark) Flash (manufactured by Rocket Japan Co., Ltd.) in a polyethylene bag, further magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) ) 0.6 g was added and mixed to obtain a mixture. This mixture is tableted with a rotary tableting machine (Vera5 / manufactured by Kikusui Seisakusho Co., Ltd.) at a pressing pressure of 1000 kgf, and one tablet has a mass of about 190 mg, a diameter of 8.0 mm, and a thickness of 3.5 mm. Tablets, round and rounded flat tablets) were obtained.
* PEARLITOR® Flash is an additive consisting of D-mannitol and corn starch.

(Example 4)
"Glycerin monostearate 12.5 g" to "glycerin monostearate 20.0 g", "obtained sizing product 23.6 g" to "obtained sizing product 24.3 g", "1 tablet mass" A tablet was obtained in the same manner as in Example 3 except that "about 190 mg" was replaced with "1 tablet having a mass of about 192 mg".

(Example 5)
"Glycerin monostearate 12.5 g" to "glycerin monostearate 25.0 g", "obtained sizing product 23.6 g" to "obtained sizing product 24.8 g", "1 tablet mass" A tablet was obtained in the same manner as in Example 3 except that "about 190 mg" was replaced with "1 tablet having a mass of about 194 mg".

The formulations of the tablets obtained in Examples 3 to 5 are listed in Table 1 below (numerical unit is mg). The numbers in Table 1 are rounded off to the nearest whole number.

(Test Example 1: Stability test for pregabalin with different particle sizes)
Amount of pregabalin-derived analog (lactam) produced from each of the pregabalin powders of Examples 1, 2 and Comparative Example 1 immediately after production and after storage for 17 days under open conditions at a temperature of 50 ° C. and a relative humidity of 75% { The ratio (%) to the total amount of pregabalin and total relatives} was measured by high performance liquid chromatography (the area percentage method was used as the quantification method). Based on the above measurement results, the results (rounded off to the first decimal place) of the increase (%) (difference) of the total analogs before and after storage under each condition are shown in Table 2 below. ..

(Test Example 2: Stability test for tableted pregabalin)
Amount of pregabalin-derived analog (lactam) produced after each tablet of Examples 3 to 5 was stored immediately after production and under open conditions at a temperature of 50 ° C. and a relative humidity of 75% for 7 days {pregavalin and total relatives The ratio (%) to the total amount of was measured by high performance liquid chromatography (the area percentage method was used as the quantification method). Based on the above measurement results, the results (rounded off to the first decimal place) of the increase (%) (difference) of the total analogs before and after storage under each condition are shown in Table 3 below. ..

From Table 2, the pregabalin powders of Examples 1 and 2 having a relatively large particle size (particularly d50 and d90 or the volume average diameter) of Comparative Example 1 having a relatively small particle size are more than the pregabalin powder of Comparative Example 1. It was revealed that the amount of pregabalin-derived relatives produced after storage under harsh conditions was significantly reduced. Therefore, in the present invention, it is newly suggested that it is particularly desired to use pregabalin having a particle size larger than that of Comparative Example 1.

Further, from Table 3, it was confirmed that even when tablets were produced using pregabalin having a relatively large particle size, the amount of pregabalin-derived analogs produced after storage under harsh conditions was sufficiently low. Therefore, it is newly suggested that the method for producing pregabalin or a preparation using the pregabalin in which the particle size distribution and the like are controlled within a predetermined range of the present invention remarkably improves the chemical stability of pregabalin.

Since the present invention has the effect of significantly improving the chemical stability of pregabalin in the preparation under harsh storage conditions, a solid preparation containing high-quality pregabalin can be produced in the medical field. Allows you to provide to.

Claims (11)

Cumulative 10% particle size (d10) in volume-based measurement measured using laser diffraction / scattering method is 3.0-45.0 μm, and cumulative 50% particle size (d50) in volume-based measurement is 9.0- . Pregavalin or a pharmaceutically acceptable salt thereof characterized by having a particle size distribution of 220.0 μm and a cumulative 90% particle size (d90) of 30.0 to 550.0 μm in volumetric measurements. It is a method for producing a solid preparation to be used.
Pregabalin or a pharmaceutically acceptable salt thereof that contains 70.0% by weight or more of pregabalin or a pharmaceutically acceptable salt thereof based on the total weight of the granulated product. A manufacturing method including a step of manufacturing a product containing . Pregavalin or its pharmaceutically acceptable salt is measured using a laser diffraction / scattering method, with a cumulative 10% particle size (d10) of 5.0 to 35.0 μm in volume-based measurement, volume-based measurement. 1 with a particle size distribution having a cumulative 50% particle size (d50) of 15.0 to 150.0 μm and a cumulative 90% particle size (d90) of 50.0 to 400.0 μm in volume-based measurement. The manufacturing method described in. The production method according to claim 1 or 2, which comprises a step of dry granulating pregabalin having the particle size distribution according to claim 1 or a pharmaceutically acceptable salt thereof. The production according to any one of claims 1 to 3 , which comprises a step of melt-granulating pregabalin having a particle size distribution according to claim 1 or a pharmaceutically acceptable salt thereof together with a low melting point oil and fat. Method. Pregabalin or a pharmaceutically acceptable salt thereof in a granule containing 90.0 to 99.0 % by weight of pregabalin or its pharmaceutically acceptable salt based on the total weight of the granulated product. The production method according to any one of claims 1 to 4, which comprises a step of producing a product containing an acceptable salt. Any of claims 1 to 5, comprising the step of tableting a mixture obtained by mixing a granule containing pregabalin or a pharmaceutically acceptable salt thereof, an excipient and a lubricant together. The manufacturing method according to paragraph 1. Cumulative 10% particle size (d10) in volume-based measurement measured using laser diffraction / scattering method is 3.0-45.0 μm, and cumulative 50% particle size (d50) in volume-based measurement is 9.0- . Pregavalin or a pharmaceutically acceptable salt thereof characterized by having a particle size distribution of 220.0 μm and a cumulative 90% particle size (d90) of 30.0 to 550.0 μm in volumetric measurements. It's mixed ,
The content of pregabalin or its pharmaceutically acceptable salt is 70.0% by weight based on the granulated product containing pregabalin or its pharmaceutically acceptable salt, based on the total weight of the granulated product. The solid preparation that is above . The cumulative 50% particle size (d50) in the volume-based measurement measured using the laser diffraction / scattering method is 15.0 to 220.0 μm , and the cumulative 90% particle size (d90) in the volume-based measurement is 50.0. The solid according to claim 7, which comprises a granulated product containing pregavalin or a pharmaceutically acceptable salt thereof and a low melting point oil / fat, which has a particle size distribution of about 550.0 μm. pharmaceutical formulation. The solid preparation according to claim 8, wherein the low melting point fat is a fatty acid ester. Amount of low melting point fat / oil in the granulated product with respect to the amount of pregabalin or its pharmaceutically acceptable salt (blending amount of low melting point fat / fat / blending of pregabalin or its pharmaceutically acceptable salt) The solid preparation according to claim 8 or 9, wherein the amount) is 0.010 to 0.18. Pregavalin or its pharmaceutically acceptable salt is measured using a laser diffraction / scattering method, with a cumulative 10% particle size (d10) of 5.0 to 35.0 μm in volume-based measurement, volume-based measurement. 7 has a particle size distribution in which the cumulative 50% particle size (d50) is 15.0 to 150.0 μm and the cumulative 90% particle size (d90) in the volume-based measurement is 50.0 to 400.0 μm. The solid preparation according to any one of 10 to 10.